The present invention relates to a kit for producing bone cement and use of the kit.
Conventional polymethylmethacrylate bone cements (PMMA bone cements) have been known for decades and are based on the ground-breaking work of Sir Charnley (Charnley, J., “Anchorage of the femoral head prosthesis of the shaft of the femur,” J. Bone Joint Surg., 42:28-30 (1960)). The basic structure of PMMA bone cements has remained the same ever since. PMMA bone cements consist of a liquid monomer component and a powder component. The monomer component generally contains (i) the monomer, methylmethacrylate, and (ii) an activator (e.g. N,N-dimethyl-p-toluidine) dissolved therein. The powder component comprises (i) one or more polymers made by polymerization, preferably suspension polymerization, based on methylmethacrylate and co-monomers, such as styrene, methylacrylate or similar monomers, (ii) a radio-opacifier, and (iii) an initiator, (for example) dibenzoylperoxide. Mixing the powder component and the monomer component, the polymers of the powder component in the methylmethacrylate swell, which generates a dough that can be shaped plastically. Simultaneously, the activator, N,N-dimethyl-p-toluidine, reacts with dibenzoylperoxide, which disintegrates and forms radicals in the process. The radicals thus formed trigger the radical polymerization of the methylmethacrylate. Upon advancing polymerization of the methylmethacrylate, the viscosity of the cement dough increases until the cement dough solidifies and thus is cured.
The essential disadvantage of the previous PMMA bone cements for the medical user is that the user needs to mix the liquid monomer component and the powder component in a mixing system or in crucibles right before applying the cement. Mixing error can easily occur in the process and adversely affect the quality of the cement. Moreover, the components must be mixed rapidly. In this context, it is important to mix all of the cement powder and monomer component without forming lumps and prevent the introduction of air bubbles during the mixing process. Unlike manual mixing, the use of vacuum mixing systems prevents the formation of air bubbles in the cement dough to a large extent. Examples of mixing systems are disclosed in U.S. Pat. No. 4,015,945, European patent application publication EP 0 674 888 A1, and Japanese patent application publication (kokai) JP 2003/181270.
However, vacuum mixing systems necessitate an additional vacuum pump and are therefore relatively expensive. Moreover, depending on the type of cement concerned, a certain waiting time is required after mixing the monomer component and the powder component until the cement dough is tack-free and can be applied. Because of the large variety of errors that can occur while mixing conventional PMMA bone cements, appropriately trained personnel are required for this purpose. The corresponding training is associated with considerable expense. Moreover, mixing of the liquid monomer component and the powder component is associated with exposure of the user to monomer vapors and particles released from the powder-like cement.
Paste-like polymethylmethacrylate bone cements, as an alternative to the conventional powder-liquid polymethylmethacrylate bone cements, have been described in unexamined German patent applications DE 10 2007 052 116 A1 and DE 10 2007 050 763 A1. The bone cements are provided to the user in the form of pre-mixed pastes that are stable during storage. In the case of paste-like two-component cements, the initiator and the accelerator are each dissolved separately in one cement paste. When the two pastes are mixed, the accelerator reacts with the initiator forming radicals that initiate the radical polymerization of the monomer in the paste. This starts the curing of the cement paste. In the case of paste-like one-component systems, the polymerization can be triggered by thermally disintegrating initiators through the action of magnetic or electromagnetic fields on ferromagnetic particles or superparamagnetic particles contained in the paste.
Initiator systems for radical polymerization of methacrylate monomers and other monomers susceptible to radical polymerization have been known for a long time.
Accordingly, German Patent DE 696 21 500 T2 discloses a combination of peroxides and metal compounds. A combination of cumene hydroperoxide, a metal compound, and thiourea is used in this context. A similar combination of thiourea and a hydroperoxide is proposed in European patent application publication EP 1 479 364 A1. In contrast, German published patent application DE 195 01 933 A1 discloses mixtures of hydroperoxides and siccatives. An interesting new system based on hydroperoxides, acylthiourea compounds, and copper salts is presented in European patent application publication EP 1 754 465 A1. The advantage of initiator systems of this type is their high thermal stability. However, hydroperoxides are irritating compounds and thus suitable only to a limited extent for initiation with PMMA bone cements directly contacting vital bone tissue.
Used with conventional PMMA bone cements that consisted of a powder component and a monomer liquid, the initiator system of dibenzoylperoxide and N,N-dimethyl-p-toluidine has proven its value in general (K.-D. Kühn, Knochenzemente für die Endoprothetik: ein aktueller Vergleich der physikalischen and chemischen Eigenschaften handelsüblicher PMMA-Zemente [Bone Cements For Endoprosthetics: An Actual Comparison of The Physical and Chemical Properties of Commercial PMMA Cements], Springer-Verlag, Berlin Heidelberg New York (2001)). In this context, dibenzoylperoxide is present as a solid in the cement powder and N,N-dimethyl-p-toluidine is dissolved in the monomer component.
However, our experiments with cement pastes using the dibenzoylperoxide/N,N-dimethyl-p-toluidine initiator system demonstrated that pastes containing N,N-dimethyl-p-toluidine have a pronounced tendency to polymerize spontaneously. Moreover, the accelerator, N,N-dimethyl-p-toluidine, that has proven its value with conventional powder/liquid polymethylmethacrylate bone cements has been the subject of some criticism due to its toxicological properties.
Aside from these redox systems, initiator systems based on the use of barbiturates have also been described. German published patent application DE 1 495 520 A1 describes a method for polymerization of vinyl compounds and polyesters. In the method, barbituric acid derivatives, halide ion donors, and copper compounds are dissolved in the monomer or mixture of monomers. In this context, the combination of barbituric acid derivative, halide ion donor, and copper compound initiates the polymerization. It is also feasible to add organic peroxides or hydrogen peroxide. Our own experiments in this context showed that initiation is also feasible in the absence of atmospheric oxygen or peroxides, which is contrary to the assumption made in DE 1 495 520, according to which air or peroxides are required to trigger the polymerization by barbiturate in the presence of copper ions and chloride ions. This means that the barbiturate itself obviously acts as initiator.
U.S. patent application publication 2003/0195273 A1 proposes a curable composition for dental applications that contains not only unsaturated monomers, but also water, a redox initiator system, and ammonium salts. The initiator system that is based on barbiturates and known from DE 1 495 520 is mentioned in this context as well.
A primer based on a monomer that can be mixed with water, a copper salt, a chloride ion donor, and thiobarbiturates as well as barbiturates has been disclosed in UK patent application publication GB 2 256 875 A. There is no evidence of the use of copper(II) hydroxide or basic copper carbonate.
A very interesting system is described in International Publication No. WO 2007/140440 A2, in which an alkali salt or alkaline earth salt of barbituric acid that is insoluble in non-acidic monomers is used in pastes. Acidic monomers acting on the barbituric acid salts release the barbiturates through a cation exchange. The barbiturates thus released react in the presence of halide ion donors with dissolved copper ions that are present in the pastes and thus initiate the radical polymerization.
A somewhat more complex system is described in DE 10 2007 050 763. In this system, alkaline earth salts of barbiturates and basic copper salts are contained in one paste. These two salts are insoluble in the methacrylate monomer. A weak organic acid, such as 2-ethylhexanoic acid, is present in a second paste. Moreover, a chloride ion donor is also present in the pastes. Mixing the two pastes, the weak organic acid simultaneously converts both the barbiturate into the soluble acid form and copper into a soluble copper salt. The advantage of this system, in particular in the case of pastes with multi-functional monomers, is that earlier diffusion and ion exchange processes allow the processing time to be increased, which otherwise is very short, usually on the order of seconds, where multi-functional monomers are used.
DE 10 2007 050 762 discloses another system for the producing bone cement. The invention described therein is based on the approach of providing two pastes which each contain a methacrylate monomer, in which a polymer that is soluble therein is dissolved and a polymer that is insoluble therein is suspended. This allows a dough-like paste to be produced that shows high internal cohesion due to the polymer being dissolved therein. In order to cure the methacrylate monomer, one of the pastes contains a radical initiator, for example a barbituric acid derivative, and the other paste contains an accelerator, for example an organic copper(II) salt. After the two pastes are mixed, activation of the initiator starts the polymerization of the methacrylate monomer, which involves the formation of bone cement with high 4-point flexural strength and high flexural modulus.
Experiments involving the use of paste-like, two-component cements containing filling agents insoluble in the methacrylate monomer, for example polymer particles, demonstrated low initial stability and an ensuing pronounced tendency to show post-cure. This effect is due to monomer that is contained in the insoluble filling agents. During the curing process, the monomer polymerizes mainly outside of the insoluble polymer particles. Subsequently, the residual monomer, as well as the dissolved initiator or the dissolved accelerator, diffuse from the polymer particles, and the monomer is then subject to post-cure. Experiments have shown that the post-cure effect is mainly caused by the paste in which the accelerator is dissolved. For this reason, it would be advantageous of providing both pastes of the two-component bone cement with initiators, if possible. However, this is associated with a technical contradiction in that the accelerator needs to make both initiators form radicals, but must, on the other hand, not trigger premature polymerization while the cement pastes are being stored.